The hearts of patients with noninsulin-dependent diabetes mellitus are highly susceptible to ischemic and hypertensive damage and are more prone to developing congestive heart failure than the nondiabetic. Since the majority of the 10 million Americans with this type of diabetes die of cardiovascular disease, it is important to begin addressing the causes underlying these cardiovascular complications. The aim of this proposal is to continue studying the consequences of one of the cardiovascular problems of noninsulin-dependent diabetes mellitus, the development of a cardiomyopathy. An animal model appropriate for the study of noninsulin-dependent diabetes mellitus-induced cardiomyopathy has been developed and partially characterized. Hearts from these animals show depressed glucose utilization, decreased glycogen levels and reduced mechanical function. In this proposal the basis for altered glucose and glycogen metabolism will be examined by measuring the content of glycolytic intermediates and tissue levels of key effectors which regulate the rate-limiting enzymes of glycolysis and glycogenolysis. The effects of chronic diabetes on total activities of these key enzymes will also be measured. The proposal will also focus on defects in lipid metabolism associated with the cardiomyopathy. Of particular interest is the effect of noninsulin-dependent diabetes on tissue content of toxic amphiphiles such as fatty acyl CoA. In a related problem, the effect of diabetes on triglyceride lipolysis and fatty acid uptake and utilization by the diabetic heart will be examined. The importance of altered lipid metabolism in the development of defects in high energy phosphate metabolism will be explored. Rats with noninsulin-dependent diabetes mellitus will be treated chronically with insulin to normalize blood glucose levels. These studies will test the efficacy of insulin therapy in reversing the abnormalities in glucose metabolism and mechanical function associated with the slowly developing cardiomyopathy observed in these animals.